Clinical nuclear medicine tests of renal perfusion and excretion using radioactive compounds are a widely used and valuable technique for diagnosing kidney disfunction. Chronic renal disease and associated renal failure today constitute a major endemic medical problem with a serious impact on health costs. Thus, the clinical assessment of renal problems using such noninvasive radionuclide procedures and, in particular, methods for early diagnosis and evaluation of renal function prior to and after therapeutic intervention have achieved general recognition in the past few years.
Although renal structure can be determined in great detail using radiography, ultrasound, and x-ray computed tomography, the critically important functional evaluation of renal disease with these modalities is not as accurate as with radionuclide techniques. Moreover, the principal virtue of the latter is not only their accuracy, but also the speed with which they can be performed, employing a noninvasive methodology with minimum discomfort to the patient and a relatively low radiation dose to pediatric as well as adult patients. In serial monitoring, such factors assume a great degree of significance.
The most important aspects of kidney function to which radionuclide procedures are applied are the estimation of glomerular filtration and of tubular function. The ligands and their corresponding Tc-99m complexes which are the subject of this invention are useful as diagnostic agents for the study of tubular secretion and, hence, renal plasma flow.
Renal plasma flow is an important parameter of kidney function that is determined by the clearance of a compound which is nearly completely extracted from the renal blood, ideally in a single transit. In practice, the measurements fall below the true renal plasma flow, because the compounds previously used do not have this property. Thus, the term effective renal plasma flow (ERPF) has come into existence. Apart from being almost completely extracted in a short period of time, the other principal requirements of such a renal diagnostic compound are that it should be rapidly excreted unchanged, that it not be extensively metabolized, and that there be no significant extrarenal pathway of excretion.
Initially, radioiodinated iodo-pyracet (Diotrast.TM.) was used for the measurement of ERPF, but its partial removal from the circulation by the liver necessitated complicated methods of quantification as well as critical probe manipulation in order to view the kidneys and exclude hepatic radioactivity. Subsequently, such radiopharmaceuticals such as Hypaque.TM. sodium and Renografin.TM. were introduced because they were not appreciably removed from circulation by the liver. Thus, a probe could be placed at the right angle to the back with relatively wide collimation and without X-ray localization of the liver. Although these substances were an improvement over Diodrast.TM., they had the disadvantage of being removed from the blood much more slowly than Diodrast.TM. which prolonged test time and decreased the effective ability of detection of kidney function differences.
Paraaminohippuric acid (PAH) is currently the compound of choice for chemical (i.e. nonradioactive) estimation of ERPF, and is generally regarded as a reference. PAH is eliminated by the kidneys partially by glomerular filtration (20%) and partially by tubular secretion (80%). Its extraction by the normal kidney is 90%, with the rest being returned by the general circulation. Because chemical analysis of PAH in blood and urine samples is cumbersome, however, this presents a disadvantage with respect to its widespread use. Additionally, this key material is not available as a radiopharmaceutical labelled with a gamma-emitting radionuclide suitable for external visualization using gamma scintillation cameras.
A related compound .sup.131 I-ortho-iodohippurate (Hippuran.TM. or OIH), available typically as the sodium salt, was found to have a lower clearance than PAH. Nevertheless, OIH has found use as a radiodiagnostic renal agent for ERPF measurements. The uptake in normal kidneys following a bolus injection is rapid, reaching a maximum within the first five minutes and, in a normally hydrated patient, will clear from the renal parenchyma and collecting system within thirty minutes. At that point, approximately 70% of the injected dose can be found in the urine. It is known, however, that this figure can vary significantly both with the state of hydration of the patient and with the disease.
A disadvantage of OIH is that the physical decay characteristics of the radionuclide .sup.131 I preclude the administration of a sufficient amount of activity to effectively study the initial perfusion of the organ after a bolus injection of the radiopharmaceutical. Despite the favorable pharmacokinetics and low background activity, the statistical accuracy of the measurements may therefore be reduced below the point where they are deemed useful. Furthermore, the principal gamma ray emitted by the radioactive label (364 keV) is higher than optimal for current detector designs, and the resolution of the image during this first phase of the renogram is poor.
Another radiopharmaceutical (.sup.99m Tc-DTPA) is now often used as an alternative to determine renal perfusion. This complex is formed when .sup.99m Tc pertechnetate is reduced in the presence of diethylenetriamine pentaacetic acid (DTPA). Because this complex is excreted exclusively by glomerular filtration, however, the images obtained can be poor in cases where the renal function is compromised. This is principally because in the normal adult glomerular filtration rate is approximately 120 ml/minute wherein the renal plasma flow as measured by PAH is about 575 ml/minute.
In practice, therefore, a compound labelled with .sup.99m Tc and which is extracted efficiently by the kidney could effectively supplant both OIH and .sup.99m Tc-DTPA, the existing agents of choice. The use of a simple radiopharmaceutical of this type would greatly decrease the duration of the test, the reagents required, and also the cost.
The radionuclide .sup.99m Tc has excellent physical decay characteristics for application in nuclear medicine, and is readily available in a radionuclide generator system. More than 80% of all diagnostic nuclear medicine procedures in the United States now involve the administration of radiopharmaceuticals labelled with this radioisotope. The 140 keV gamma ray emitted in 89% of all disintegrations of this metastable nuclear state is well matched to the properties of modern scintillation camera systems, and the level of nonpenetrating radiation following decay gives a low absorbed radiation dose to the recipient. In turn, this means that large amounts of radioactivity can be administered leading to more reliable statistics in quantitative studies. Thus, serial monitoring also is possible with technetium. Additionally, the halflife of 6.02 hours is better matched to the length of the study than that of .sup.131 I (8 days). In the chemical form of pertechnetate (.sup.99m TcO.sub.4.sup.-), however, its absolute concentration in the renal parenchyma is low and imaging studies have poor resolution. In addition, urinary excretion of pertechnetate is relatively slow, about 86% of the filtered activity being reabsorbed by the renal tubules and, hence, pertechnetate per se cannot be employed efficiently for renal function studies.
Therefore, an agent labelled with .sup.99m Tc and having a renal extraction comparable to or greater than OIH is highly desirable because it would allow diagnostic information to be obtained from all three portions of the renogram: the vascular (tracer appearance), the tubular reabsorption (blood flow), and the excretion (drainage) phases. The expected clinical applications would include, for example, the screening of hypertensive patients for unilateral renal disease, the detection of obstructive lesions, the early diagnosis of renal transplant rejection, the monitoring of urinary transit, etc. Furthermore, because of the low radiation dose, such studies may be carried out in pediatric patients or during pregnancy.
A bisamide bisthiol (N.sub.2 S.sub.2) chelate that forms a complex with reduced technetium, [.sup.99m TcO(ema)].sup.-, was described as a potential renal agent by Davison et al J. Nucl. Med. 20(60), 641 (1979). It was subsequently shown to be excreted into both the urine and bile in a chemically unchanged form, Jones et al J. Nucl. Med. 23(9), 801 (1982), thus fulfilling one of the requirements for a renal agent. Fritzberg evaluated [TcO(ema)].sup.- in renal transplant patients and found that, although the images were excellent, there were 7 to 10% of the material clearing into bile and this interfered with evaluation of the kidneys in their normal position. Thus, a single agent for determining renal function is still being sought.